1. Field of the Invention
This invention relates to the treatment and/or prevention of Parkinson's disease dementia (PDD) with ceftriaxone. A daily dosage of ceftriaxone for the treatment and/or prevention of PDD of a human subject according to this invention ranges from about 1.5 mg/kg to about 35 mg/kg.
2. Description of the Related Art
Dementia can be classified into the following two categories based on the part of the brain which is influenced: (1) cortical dementia, for example, Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Frontal-temporal dementia (FTD), etc.; and (2) subcortical dementia, for instance, Parkinson's disease dementia (PDD), Huntington's disease (HD), etc.
Parkinson's disease (PD) is a common neurodegenerative disease, and the clinical symptoms thereof include resting tremor, rigidity, bradykinesia, and postural instability. The pathogenesis of PD might be related to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and formation of Lewy bodies. Cardinal motor symptoms occur in patients with PD. In addition, about 25-50% of the aforesaid patients develop impairment of cognitive functions, which further leads to dementia (i.e. PDD). The impairment of cognitive functions regarding patients with PDD includes impairment in attention, working memory, executive functions, constructional abilities, and visuospatial functions.
The neuropsychological difference between patients with AD and PDD has been investigated in numerous studies, in particular, the difference in the impairment of cognitive functions. For instance, primacy of memory loss is a typical symptom of AD, but not a typical symptom of PDD. However, disturbances in attention, motivation, and access and manipulation of knowledge, and psychomotor slowing all are typical symptoms of PDD (Song I. U. et al. (2008), Eur.Neurol., 59:49-54). Furthermore, a document has reported that: compared to patients with AD, the patients with PDD have instrumental functions (such as language and praxis) which are less impaired, verbal fluency and visuospatial functions (e.g., visual perception) which are more impaired, and hallucination which is more sever, and commonly suffer from personality change and depressive symptoms (Emre M. (2003), Lancet Neurology, 2:229-237).
The conventional drug commonly used clinically to treat PDD is rivastigmine (brand name Exelon®). However, rivastigmine is only able to cure mild or moderate PDD, and might cause symptoms of PD (in particular, tremor) to worsen. Moreover, the conventional drug Levodopa (L-dopa) commonly used clinically to ameliorate motor symptoms of PD has a limited therapeutic effect on impairment of cognitive functions (Emre M. (2003), supra). Therefore, it is inevitable to develop or find a drug that is capable of being effective in treating PDD.
Ceftriaxone is a broad-spectrum β-lactam antibiotic and is commonly used clinically to treat infections arising from Gram-positive and Gram-negative bacteria. In recent years, the treatment of neurodegenerative diseases (e.g., PD and dementia) with ceftriaxone has been noticed. For example, the doctoral dissertation completed by Leung Cheuk Hung in 2007 while attending Hong Kong Baptist University (name: Glutamate Antagonism as a Potential Treatment of Parkinson's Disease: A Study in a Rat Model) reports that ceftriaxone was applied to 6-hydroxydopamine (6-OHDA)-lesioned rats (an animal model of PD). The experimental results of the aforesaid dissertation indicates that ceftriaxone is useful in amelioration of motor symptoms and neuroprotection of dopaminergic neurons.
U.S. 2004/0191803 A1 discloses a method of treating impaired cognitive function in a mammal, which comprises the step of administering a therapeutically effective amount of ceftriaxone or an analog or derivative thereof to the aforesaid mammal. The aforementioned impaired cognitive function may be associated with the following diseases or disorders: mild cognitive impairment (MCI), age related cognitive decline (ARCD), memory loss, senility, and dementia (e.g., DLB, vascular dementia, AD, and HIV associated dementia). Particularly, in the examples of the aforesaid prior art document, aged-impaired (AI) rats were treated with ceftriaxone at a daily dose of 200 mg/kg for 7 days. The experimental result shows that ceftriaxone is able to ameliorate cognitive impairment of the AI rats.
In Hota S. K. et al. (2008), Neurobiology of Learning and Memory, 89:522-532, rats chronically exposed to hypobaric hypoxia were treated with ceftriaxone. The experimental result reveals that ceftriaxone is capable of ameliorating the cognitive impairment resulting from hypobaric hypoxia, reducing oxidative stress in the hippocampus, and decreasing neuronal degeneration and chromatin condensation. Consequently, ceftriaxone is expected to be useful for treating AD and ischemic and hypoxic conditions that are associated with excitotoxicity.
As far as the inventor is aware, so far, there have been no documents or prior art patents which disclose that ceftriaxone can be utilized in the treatment of PDD. Through research, the inventor has found that cognitive functions (such as working memory and recognition ability) of rats having PDD can be ameliorated by administering ceftriaxone at a daily dosage ranging from 10 to 200 mg/kg. Accordingly, the inventor deduces that ceftriaxone is useful in the treatment and/or prevention of PDD in a human subject at a specific dosage.